The present invention relates to new benzenesulphonamide compounds, and to pharmaceutical compositions containing them.
The compounds of the present invention have a novel structure giving them a TXA2 receptor antagonist and 5HT2 serotoninergic receptor antagonist character.
Compounds having a benzenesulphonamide chain have been described in Application EP 864 561 in relation to their NO-yielding character and their thromboxane A2 (TXA2) receptor antagonist character, as well as in Applications EP 648 741 or WO 9406761 solely in relation to their TXA2 receptor antagonist properties.
Platelet aggregation and vasospasms play an essential role in the aetiology and development of atherothrombotic cardiovascular diseases. TXA2, an arachidonic acid metabolite, and serotonin (5HT), a neurotransmitter, are both powerful vasoconstrictor agents, and are able to induce or reinforce platelet activation, resulting in the aggregation thereof The vasoconstrictor and pro-aggregation actions of TXA2 are effected through the intermediary of membrane receptors called TP receptors (Medicinal Research Reviews, 1991, 11 5, p. 503) while those of serotonin are effected through the intermediary of 5HT1 or 5HT2 receptors (T.I.P.S., 1991, 121, p. 223). Research strategies pursued with the aim of finding agents that block the production and/or activation of TXA2 have led to the development of selective TP receptor antagonists, of TXA2-synthase inhibitors, or of mixed agents that exhibit both properties (Medicinal Research Reviews, ibid., T.I.P.S., 1991, 121, 158). Like TXA2, serotonin acts by stimulating platelets and vascular constriction and its activity is found to be increased in atherothrombotic diseases.
The idea of compounds that oppose both the process that causes thromboxane to become active and the process that causes serotonin to become active is extremely useful for the clinician. Such products have the advantage of offering more complete protection both against the activation of platelets and against vasospasms. It will thus be possible for such products to be used in the treatment of pathologies associated with increased activity of TXA2 and 5-HT especially in the treatment of atherothrombotic cardiovascular diseases, such as myocardial infarction, angina pectoris, cerebral vascular accidents, Raynaud""s disease, and also asthma and bronchospasms, as well as migraine and venous diseases.
The present invention relates to the compounds of formula (I): 
wherein:
G represents a group such as: 
wherein R1 and R2 independently represent a hydrogen atom, or an alkyl, cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, cycloalkyl, cycloalkylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl group, or
R1 and R2 together with the nitrogen atom form a heterocycloalkyl group of formula 
having from 5 to 7 ring members, wherein Y represents a nitrogen atom, an oxygen atom or a CH2 group and R6 represents a hydrogen atom or an alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted arylcarbonyl, optionally substituted arylcarbonylalkyl, optionally substituted diarylalkyl, optionally substituted diarylalkenyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl, optionally substituted heteroarylcarbonyl or optionally substituted heteroarylcarbonylalkyl group,
R3 represents a hydrogen atom or an alkyl or optionally substituted phenyl group,
Ra represents a hydroxy, alkoxy, optionally substituted aryloxy, optionally substituted arylalkyloxy, amino, alkylamino, dialkylamino, optionally substituted arylamino or optionally substituted arylalkylamino group,
Rb and Rc, which may be identical or different, each represents a hydrogen atom, a halogen atom, an alkyl group, an alkoxy group, a hydroxy group or a trihaloalkyl group,
m is an integer of from 0 to 1 inclusive,
n and q are identical or different integers of from 0 to 6 inclusive,
p and r are identical or different integers of from 1 to 6 inclusive,
to their enantiomers and diastereoisomers, and also to addition salts thereof with a pharmaceutically acceptable acid or base,
wherein:
the term xe2x80x9calkylxe2x80x9d denotes a linear or branched chain having from 1 to 6 carbon atoms,
the term xe2x80x9calkoxyxe2x80x9d denotes a linear or branched alkyl-oxy group having from 1 to 6 carbon atoms,
the term xe2x80x9ctrihaloalkylxe2x80x9d denotes a carbon chain having from 1 to 3 carbon atoms and from 1 to 3 identical or different halogen atoms,
the term xe2x80x9calkenylxe2x80x9d denotes a chain having from 2 to 6 carbon atoms and containing from 1 to 3 double bonds,
the term xe2x80x9ccycloalkylxe2x80x9d denotes a saturated cyclic group having from 3 to 8 carbon atoms,
the term xe2x80x9carylxe2x80x9d denotes a phenyl or naphthyl group,
the term xe2x80x9cheteroarylxe2x80x9d denotes an aromatic monocyclic group, or a bicyclic group in which at least one of the rings is aromatic, having from 5 to 11 ring members and from 1 to 5 hetero atoms selected from nitrogen, oxygen and sulphur,
the terms xe2x80x9cdiarylalkylxe2x80x9d and xe2x80x9cdiarylalkenylxe2x80x9d denote, respectively, alkyl and alkenyl groups as defined hereinbefore, substituted by two identical or different aryl groups as defined hereinbefore,
the term xe2x80x9csubstitutedxe2x80x9d relating to phenyl, aryl, arylalkyl, arylcarbonyl, arylcarbonylalkyl, diarylalkyl, diarylalkenyl, heteroaryl, heteroarylalkyl, heteroarylcarbonyl, heteroarylcarbonylalkyl, arylamino and arylalkylamino denotes that the groups in question are substituted in the aromatic moiety by one or two identical or different substituents selected from halogen atoms and alkyl groups, alkoxy groups, hydroxy groups, cyano groups, nitro groups, amino groups (optionally substituted by one or two alkyl groups) and groups C(O)Rd, Rd representing a group selected from hydroxy, alkoxy and amino, wherein the heteroaryl and heteroarylalkyl groups may also be substituted by an oxo group in the non-aromatic moiety of the heteroaryl.
Amongst the pharmaceutically acceptable acids there may be mentioned, without implying any limitation, hydrochloric, hydrobromic, sulphuric, phosphonic, acetic, trifluoroacetic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, tartaric, maleic, citric, ascorbic, methanesulphonic, camphoric acid, etc.
Amongst the pharmaceutically acceptable bases there may be mentioned, without implying any limitation, sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine etc.
Preferred compounds of formula (I) are those wherein, taken together or separately, the value of p is 2, the value of q is 2, the substituent R3 represents a hydrogen atom, the substituent Ra represents a hydroxy group, the substituent Rb represents a halogen atom and the substituent Rc represents a hydrogen atom.
An especially advantageous embodiment of the invention relates to compounds of formula (I) wherein p and q are each 2, Ra represents a hydroxy group, R3 and Rc each represents a hydrogen atom, Rb represents a halogen atom and G represents an amino, dialkylamino or arylalkylamino group or a heterocycloalkyl group of formula: 
wherein Y represents a nitrogen atom, an oxygen atom or a CH2 group and R6 is selected from a hydrogen atom and the groups optionally substituted aryl and optionally substituted heteroaryl.
In preferred compounds of formula (I), G represents a dialkylamino group.
Other preferred compounds of formula I are those wherein G represents a substituted heterocycloalkyl group 
wherein: 
represents a group having 5 or 6 ring members, such as: pyrrolyl, morpholino, piperidyl or piperazinyl,
and R6 substituted on a carbon or nitrogen atom of the heterocycloalkyl represents a hydrogen atom, a phenyl substituent optionally substituted by a halogen atom, or a heteroaryl group having 9 ring members that contains one or two hetero atoms selected from nitrogen, oxygen and sulphur and is optionally substituted by a halogen atom.
Preferred compounds of formula (I) are those wherein the optionally substituted heteroaryl group represents a benzisoxazolyl group optionally substituted by a halogen atom, or a benzisothiazolyl group optionally substituted by a halogen atom.
Advantageously, the invention relates to compounds of formula (I) wherein, taken together or separately, the substituent Gxe2x80x94(CH2)rxe2x80x94Oxe2x80x94 is attached to one of the two carbon atoms 2 or 4 of the phenyl group, the substituent 
is attached to the 5xe2x80x2 carbon atom of the phenyl group, and Rb is attached to the 4xe2x80x3 atom of the phenyl group.
Of the preferred compounds of the invention, the following may be mentioned:
3-[3-(2-{[(4-chlorophenyl)sulphonyl]amino}ethyl)-5-(2-{2-[3-(dimethylamino)-propoxy]phenyl}ethyl)phenyl]propanoic acid
3-[3-(2-{[(4-chlorophenyl)sulphonyl]amino}ethyl)-5-(2-{2-[2-(1-pyrrolidinyl)-ethoxy]phenyl}ethyl)phenyl]propanoic acid
3-[3-(2-{[(4-chlorophenyl)sulphonyl]amino}ethyl)-5-(2-{2-[2-(4-morpholinyl)-ethoxy]phenyl}ethyl)phenyl]propanoic acid.
The present invention relates also to a process for the preparation of compounds of formula (I) which is characterised in that:
1) when it is desired to obtain compounds of formula (I) wherein m=0 and n is other than 1, there is used as starting material a compound of formula (II): 
wherein R3 is as defined for formula (I), Rxe2x80x2a represents a linear or branched (C1-C6)alkyl group, WO-L represents a group of formula: 
in which W represents a hydrogen atom or a benzyl group, pxe2x80x2 and qxe2x80x2 are integers of from 0 to 3, and nxe2x80x2+nxe2x80x3=an integer of from 0 to 3 provided that, when nxe2x80x2 is 0, nxe2x80x3 is 0, 2 or 3,
which is catalytically reduced to yield, after debenzylation when W represents a benzyl group, a compound of formula (III): 
wherein R3, n, p and q are as defined for formula (I) and Rxe2x80x2a represents a linear or branched (C1-C6)alkyl group,
which is condensed in basic medium with a halide of formula: Gxe2x80x94(CH2)rxe2x80x94X, wherein X represents a halogen atom, to yield a compound of formula (IV): 
wherein G, R3, n, p, q and r are as defined for formula (I) and Rxe2x80x2a represents a linear or branched (C1-C6)alkyl group,
which is deprotected by cleavage of the phthalimido group in the presence of hydrazine to yield the corresponding amine which, in turn, is reacted with an optionally substituted benzenesulphonyl halide of formula: 
wherein Rb and Rc are as defined for formula (I) and X represents a halogen atom, to yield a compound of formula (I/a), a particular case of the compounds (I): 
wherein G, Rb, Rc, R3, r, n, p and q are as defined for formula (I) and Rxe2x80x2a represents a linear or branched (C1-C6)alkyl group,
2) when it is desired to obtain compounds of formula (I) wherein m=1, or wherein m=0 and n=1, there is used as starting material a compound of formula (II/a): 
wherein R3 is as defined for formula (I), Rxe2x80x2a represents a linear or branched (C1-C6)alkyl group, HO-Lxe2x80x2 represents a group of formula: HOxe2x80x94(CH2)nxe2x80x94, qxe2x80x2 and pxe2x80x2 are integers of from 0 to 3 and n is an integer of from 0 to 6,
which is reduced catalytically and halogenated to yield a compound (V): 
wherein R3, n, p and q are as defined for formula (I), Rxe2x80x2a represents a linear or branched (C1-C6)alkyl group and X represents a halogen atom, which compound of formula (V)
either, when m=1, is subjected to the nucleophilic attack of a compound of formula: 
to yield a compound of formula (VI): 
in which formulae G, R3, n, p, q and r are as defined for formula (I) and Rxe2x80x2a represents a linear or branched (C1-C6)alkyl group,
which is deprotected by cleavage of the phthalimido group in the presence of hydrazine to yield the corresponding amine which, in turn, is reacted with an optionally substituted benzenesulphonyl halide of formula: 
wherein X represents a halogen atom to yield a compound of formula (I/b), a particular case of the compounds of formula (I): 
wherein G, Rb, Rc, R3, n, p, q and r are as defined for formula (I) and Rxe2x80x2a represents a linear or branched (C1-C6)alkyl group,
or, when m=0 and n=1, is subjected to the action of a compound of formula 
to yield, after debenzylation, a compound of formula (VII): 
wherein R3, p and q are as defined for formula (I) and Rxe2x80x2a represents a linear or branched (C1-C6)alkyl group,
which is condensed in basic medium with a halide of formula Gxe2x80x94(CH2)rxe2x80x94X wherein X represents a halogen atom to yield a compound of formula (VIII): 
wherein G, R3, p, q and r are as defined for formula (I) and Rxe2x80x2a represents a linear or branched (C1-C6)alkyl group,
which is deprotected by cleavage of the phthalimido group in the presence of hydrazine to yield the corresponding amine which, in turn, is reacted with an optionally substituted benzenesulphonyl halide of formula: 
to yield a compound of formula (I/c), a particular case of the compounds (I): 
wherein G, Rb, Rc, R3, p, q and r are as defined for formula (I) and Rxe2x80x2a represents a linear or branched (C1-C6)alkyl group,
which compounds of formula (I/a), (I/b) or (I/c) may be subjected to hydrolysis of the ester function, in acidic or basic medium according to the reactive groups present in the molecule, to yield a compound of formula (I/d): 
a particular case of the compounds of formula (I) wherein G, Rb, Rc, R3, m, n, p, q and r are as defined for formula (I),
which compounds (I/a), (I/b), (I/c) and (I/d) constitute the totality of the compounds of formula (I) and:
may, if desired, be purified according to a conventional purification technique,
are optionally separated into their stereoisomers according to a conventional separation technique,
are, if desired, converted into their addition salts with a pharmaceutically acceptable acid or base,
it being understood that, at any point considered appropriate during the course of the process described above, the carboxylic acid function may be esterified or the carboxylic ester function may be hydrolysed to the corresponding acid, which may be converted again to a different ester as required by the synthesis.
The present invention relates also to pharmaceutical compositions comprising as active ingredient at least one compound of formula (I), alone or in combination with one or more pharmaceutically acceptable, inert, non-toxic excipients or carriers.
Amongst the pharmaceutical compositions according to the invention there may be mentioned more especially those which are suitable for oral, parenteral or nasal administration, tablets or dragees, sublingual tablets, gelatin capsules, lozenges, suppositories, creams, ointments, dermal gels, etc.
The useful dosage varies in accordance with the age and weight of the patient, the nature and the severity of the disorder and also the administration route, which may be oral, nasal, rectal or parenteral. Generally, the unit dosage ranges from 0.1 mg to 500 mg for a treatment of from 1 to 3 administrations per 24 hours.
The following Examples illustrate the invention and do not limit it in any way. The structures of the described compounds have been confirmed by customary spectroscopic and spectrometric techniques.
The starting materials employed are known products or products prepared according to known procedures.
Step a: 3,5-Dibromobenzaldehyde
0.222 mol of a solution of n-butyllithium in hexane is added dropwise at xe2x88x9280xc2x0 C. to 0.222 mol of 1,3,5-tribromobenzene in 1.8 liters of ethyl ether. The reaction mixture is stirred at xe2x88x9280xc2x0 C. for one hour. A solution of 0.222 mol of N,N-dimethylformamide in 50 ml of ethyl ether is slowly added. The temperature is maintained at xe2x88x9280xc2x0 C. for one hour, before being brought to ambient temperature. Stirring is carried out for one night. 450 ml of 1N hydrochloric acid are added. The reaction mixture is extracted with ether. The organic phases are collected and dried over magnesium sulphate. After filtration and removal of the solvents by evaporation, the crude product is purified by chromatography on a silica column (eluant: cyclohexane/ethyl acetate: 95/5).
Step b: 2-[(E)-2-(3,5-Dibromophenyl)ethenyl]phenol
0.474 mol of a solution of n-butyllithium in hexane is added at +5xc2x0 C. to 0.237 mol of (2-hydroxybenzyl)(triphenyl)phosphonium bromide in 1.2 liters of THF. The reaction mixture is maintained at +5xc2x0 C. for one hour and then 0.21 mol of the compound obtained in the above Step dissolved in 360 ml of THF is added dropwise. The reaction mixture is slowly brought to ambient temperature and then hydrolysed and extracted with ethyl ether. The organic phases are collected and dried over magnesium sulphate. After filtration and removal of the solvents by evaporation, the crude product is purified by chromatography on a silica column (eluant: cyclohexane/ethyl acetate: 95/5).
Step c: 3-Bromo-5-[(E)-2-(2-hydroxyphenyl)ethenyl]benzaldehyde
0.378 mol of a solution of n-butyllithium in hexane is slowly added at xe2x88x9280xc2x0 C. to 0.172 mol of the compound obtained in the above Step in 3 liters of ethyl ether. The reaction mixture is maintained at xe2x88x9280xc2x0 C. for one hour and then 0.172 mol of N,N-dimethylformamide dissolved in 100 ml of ether is slowly added. The reaction mixture is maintained at that temperature for one hour and is then brought to +10xc2x0 C. to be hydrolysed by a 1N hydrochloric acid solution. The mixture is extracted with ethyl ether, and the organic phases are collected and dried over magnesium sulphate. After filtration and removal of the solvents by evaporation, the crude product is purified by chromatography on silica (eluant: cyclohexane/ethyl acetate: 90/10).
Step d: tert-Butyl (2E)-3-{3-bromo-5-[(E)-2-(2-hydroxyphenyl)ethenyl]phenyl}-2-proenoate
0.3 mol of tert-butyl (triphenylphosphoranylidene)acetate is added to 0.15 mol of the compound obtained in the above Step in 2 liters of toluene. The reaction mixture is heated at reflux for 2 hours. The solvents are evaporated off and the crude product is purified by chromatography on a silica column (eluant: cyclohexane/ethyl acetate: 85/15).
Step e: tert-Butyl (2E)-3-{3-[(E)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethenyl]-5-[(E)-2-(2-hydroxyphenyl)ethenyl]phenyl}-2-propenoate
0.1607 mol of the compound obtained in the above Step, 0.016 mol of palladium acetate, 0.032 mol of tris(2-methylphenyl)phosphine, 0.402 mol of diisopropylamine and 0.1607 mol of vinylphthalimide are added in succession to 2.5 liters of N,N-dimethylformamide and 10 ml of water. The reaction mixture is heated at reflux for 3 hours and then brought to ambient temperature. After hydrolysis, the mixture is adjusted to pH 4 using a dilute hydrochloric acid solution and then extracted with dichloromethane. The organic phases are collected and dried over magnesium sulphate. After filtration and removal of the solvents by evaporation, the crude product is purified by chromatography on silica (eluant: cyclohexane/ethyl acetate: 70/30).
Step a: 3,5-Dibromobenzaldehyde
The product is obtained in accordance with the same procedure as that described in Preparation A, Step a.
Step b: (3,5-Dibromophenyl)methanol
0.506 mol of sodium borohydride is added in portions to 0.3 mol of the compound obtained in the above Step in 650 ml of methanol and 200 ml of THF while maintaining the temperature at +30xc2x0 C. After stirring for 4 hours, 300 ml of a saturated NaHCO3 solution are added. The solvents are evaporated off. The solid obtained is filtered off, washed with water and dried.
Step c: 3-Bromo-5-(hydroxymethyl)benzaldehyde
0.628 mol of n-butyllithium is added at xe2x88x9280xc2x0 C. to 0.285 mol of the compound obtained in the above Step in 2.3 liters of ether. The reaction mixture is maintained at that temperature for 4 hours 30 minutes. 22 ml of DMF dissolved in 100 ml of ether are added at xe2x88x9280xc2x0 C. The mixture is maintained at xe2x88x9280xc2x0 C. for 1 hour before being allowed to return to a temperature of +10xc2x0 C. A 1N hydrochloric acid solution is added until an acid pH is obtained. The mixture is decanted, extracted with ethyl ether and dried over magnesium sulphate. The crude product is purified by chromatography (eluant: cyclohexane/ethyl acetate: 80/20).
Step d: tert-Butyl (2E)-3-[3-bromo-5-(hydroxymethyl)phenyl]-2-propenoate
0.35 mol of tert-butyl (triphenylphosphoranylidene)acetate is added to 0.175 mol of the compound obtained in the above Step in 1.65 liters of toluene. The reaction mixture is heated at reflux for 3 hours. The solvents are evaporated off. The crude product is taken up in isopropyl ether and heated at reflux for 1 hour. After cooling slowly, the precipitate is filtered off. The filtrate is evaporated and the crude product is purified by chromatography on a silica column (eluant: cyclohexane/ethyl acetate: 85/15).
Step e: tert-Butyl (2E)-3-[3-[(E)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethenyl]-5-(hydroxymethyl)phenyl]-2-propenoate
The procedure is identical to that used in Preparation A, Step e.
Step a: (3,5-Dibromobenzyl)(triphenyl)phosphonium bromide
0.20 mol of triphenylphosphine hydrobromide is added in portions to 0.20 mol of the compound obtained in Preparation A, Step a, in 800 ml of acetonitrile. The mixture is heated at reflux for 24 hours and then cooled. The solvent is subsequently evaporated off and the precipitate is filtered off and then dried.
Step b: [2-(Benzyloxy)phenyl]acetaldehyde
0.104 mol of hydroxy-1-oxo-benzo[d][1,2]iodoxol-3-one is added to 0.08 mol of [2-(2-benzyloxy)phenyl]ethanol in 500 ml of tetrahydrofuran. The reaction mixture is heated at reflux for 2 hours and then cooled. The precipitate is filtered off and the filtrate is evaporated.
Step c: 1-{(2E)-3-[2-(Benzyloxy)phenyl]-2-propenyl}-3,5-dibromobenzene
0.13 mol of potassium tert-butoxide is added in portions to 0.13 mol of the compound obtained in Step a in 800 ml of tetrahydrofuran. The reaction mixture is stirred for 30 minutes at ambient temperature and then 0.066 mol of the compound obtained in the above Step is added. After stirring for 12 hours, 150 ml of water are added and then extraction is carried out with dichloromethane. The organic phases are collected and dried over magnesium sulphate. The product is purified by chromatography on silica (eluant: cyclohexane/dichloromethane: 80/20).
Step d: tert-Butyl (2E)-3-(3-{(2E)-3-[2-(benzyloxy)phenyl]-2-propenyl}-5-bromophenyl)-2-propenoate
The procedure is identical to that used in Preparation A, Steps c and d.
Step e: tert-Butyl (2E)-3-{3-{(2E)-3-[2-(benzyloxy)phenyl]-2-propenyl}-5-[(E)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2yl)ethenyl]phenyl}-2-propenoate
The procedure is identical to that used in Preparation A, Step e.